"Sickle Cell Anemia, a Molecular Disease" is a 1949 scientific paper by Linus Pauling, Harvey A. Itano, Seymour J. Singer and Ibert C. Wells that established sickle-cell anemia as a genetic disease in which affected individuals have a different form of the metalloprotein hemoglobin in their blood. The paper, published in the November 25, 1949 issue of Science, reports a difference in electrophoretic mobility between hemoglobin from healthy individuals and those with sickle-cell anemia, with those with sickle cell trait having a mixture of the two types. The paper suggests that the difference in electrophoretic mobility is probably due to a different number of ionizable amino acid residues in the protein portion of hemoglobin (which was confirmed in 1956 by Vernon Ingram), and that this change in molecular structure is responsible for the sickling process. It also reports the genetic basis for the disease, consistent with the simultaneous genealogical study by James V. Neel: those with sickle-cell anemia are homozygous for the disease gene, while heterozygous individuals exhibit the usually asymptomatic condition of sickle cell trait. [1]
The paper introduced the concept of a "molecular disease", and is considered a major impetus to the development of molecular medicine. The paper helped establish that genes control not just the presence or absence of enzymes (as genetics had shown in the early 1940s) but also the specific structure of protein molecules. [2] It was also an important triumph in the efforts of Pauling and others to apply the instruments and methods of the physical sciences to biology, and Pauling used it promote such research and attract funding. [3]
Linus Pauling was a prominent physical chemist at the California Institute of Technology (a main focal point of Warren Weaver's efforts to promote what he called "molecular biology" through Rockefeller Foundation grants). In the mid-1930s, Pauling turned his attention to the physical and chemical nature of hemoglobin. In 1946, he set graduate student Harvey Itano (who had been previously trained as a physician) the task of finding differences in hemoglobin that might explain sickle cell disease. After failing to find any differences in size, weight, or acid-base titration (despite the advanced instruments available at Caltech), Itano found that oxygen could inhibit the sickling process while various reducing agents could speed it up; this was the basis of Pauling and Itano's first publication on the disease. Itano also found that the globin portion of sickle cell hemoglobin had a barely detectable difference in electrical charge. [4]
To measure this electrical difference precisely, Pauling assigned graduate student John Singer to work with Itano and another medical researcher, Ibert C. Wells, before Pauling left in early 1948 for a guest lectureship in England. Using a "Tiselius Apparatus" to perform free-boundary electrophoresis, Pauling's three researchers were able to estimate that molecules of sickle-cell hemoglobin had about three more positive charges than normal hemoglobin. [3] [4] They also estimated that blood from those with sickle cell trait was a mixture of 60 percent normal hemoglobin and 40 percent sickle-cell hemoglobin. [1] Near the end of the project, they learned of parallel results by geneticist James V. Neel, who demonstrated the inheritance pattern of the disease by traditional genetic methods; both Neel's work and that of Pauling's group were published in the same issue of Science. [3]
Following the 1949 paper, Itano left the Pauling laboratory to work with Neel; in the following years Itano and Neel used electrophoresis to identify a number of other human hemoglobin variants, including some associated with other diseases. At Caltech, a comparison of the amino acid content of normal and sickle cell hemoglobins showed that there were several differences in chemical makeup, but did not explain the difference in electric charge that made electrophoretic separation possible. The cause of this difference was pinpointed in 1956 and 1957, when Vernon Ingram used protein fingerprinting (a combination of electrophoresis and chromatography) to show that the key difference between normal hemoglobins and sickle cell hemoglobins was a single difference in one chain of the protein: a glutamic acid residue on the normal hemoglobin in place of a valine residue on the sickle cell hemoglobin. [5]
The molecular disease concept put forward in the 1949 paper also became the basis for Linus Pauling's view of evolution. In the 1960s, by which time it had been shown that sickle cell trait confers resistance to malaria and so the gene had both positive and negative effects and demonstrated heterozygote advantage, Pauling suggested that molecular diseases were actually the basis of evolutionary change. [6] He also advocated eugenic policies, such as marking all who carry the sickle cell trait and other molecular disease genes, to reduce the number of children born with genetic diseases. [7]
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Linus Carl Pauling was an American chemist, biochemist, chemical engineer, peace activist, author, and educator. He published more than 1,200 papers and books, of which about 850 dealt with scientific topics. New Scientist called him one of the 20 greatest scientists of all time, For his scientific work, Pauling was awarded the Nobel Prize in Chemistry in 1954. For his peace activism, he was awarded the Nobel Peace Prize in 1962. He is one of five people to have won more than one Nobel Prize. Of these, he is the only person to have been awarded two unshared Nobel Prizes, and one of two people to be awarded Nobel Prizes in different fields, the other being Marie Curie.
Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.
Fetal hemoglobin, or foetal haemoglobin is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream to organs and tissues in the fetus. It is produced at around 6 weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition than adult forms of hemoglobin, allowing it to bind oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother's bloodstream, which occurs through the placenta found in the mother's uterus.
Émile Zuckerkandl was an Austrian-born French biologist considered one of the founders of the field of molecular evolution. He introduced, with Linus Pauling, the concept of the "molecular clock", which enabled the neutral theory of molecular evolution.
Vernon Martin Ingram, was a German–American professor of biology at the Massachusetts Institute of Technology.
Hemoglobin C is an abnormal hemoglobin in which glutamic acid residue at the 6th position of the β-globin chain is replaced with a lysine residue due to a point mutation in the HBB gene. People with one copy of the gene for hemoglobin C do not experience symptoms, but can pass the abnormal gene on to their children. Those with two copies of the gene are said to have hemoglobin C disease and can experience mild anemia. It is possible for a person to have both the gene for hemoglobin S and the gene for hemoglobin C; this state is called hemoglobin SC disease, and is generally more severe than hemoglobin C disease, but milder than sickle cell anemia.
Hemoglobin electrophoresis is a blood test that can detect different types of hemoglobin. The test can detect hemoglobin S, the form associated with sickle cell disease, as well as other abnormal types of hemoglobin, such as hemoglobin C. It can also be used to investigate thalassemias, which are disorders caused by defective hemoglobin production.
Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene, but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele. Those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin.
Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.
Seymour Jonathan Singer was an American cell biologist and professor of biology, emeritus, at the University of California, San Diego.
Molecular medicine is a broad field, where physical, chemical, biological, bioinformatics and medical techniques are used to describe molecular structures and mechanisms, identify fundamental molecular and genetic errors of disease, and to develop molecular interventions to correct them. The molecular medicine perspective emphasizes cellular and molecular phenomena and interventions rather than the previous conceptual and observational focus on patients and their organs.
Robert Brainard Corey was an American biochemist, mostly known for his role in discovery of the α-helix and the β-sheet with Linus Pauling. Also working with Pauling was Herman Branson. Their discoveries were remarkably correct, with even the bond lengths being accurate until about 40 years later. The α-helix and β-sheet are two structures that are now known to form the backbones of many proteins.
William Bosworth Castle was an American physician and physiologist who transformed hematology from a "descriptive art to a dynamic interdisciplinary science."
James Van Gundia Neel was an American geneticist who played a key role in the development of human genetics as a field of research in the United States. He made important contributions to the emergence of genetic epidemiology and pursued an understanding of the influence of environment on genes. In his early work, he studied sickle-cell disease and thalassemia conducted research on the effects of radiation on survivors of the Hiroshima atomic bombing.
Harvey Akio Itano was an American biochemist best known for his work on the molecular basis of sickle cell anemia and other diseases. In collaboration with Linus Pauling, Itano used electrophoresis to demonstrate the difference between normal hemoglobin and sickle cell hemoglobin; their 1949 paper "Sickle Cell Anemia, a Molecular Disease" was a landmark in both molecular medicine and protein electrophoresis, though the use of electrophoresis to separate hemoglobin variants had been pioneered by Maud Menten and collaborators some years earlier.
Sickle cell disease (SCD), one of the hemoglobinopathies, is a group of blood disorders typically inherited. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain, anemia, swelling in the hands and feet, bacterial infections, and stroke. Long-term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years.
Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most common alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.
Hemoglobin Lepore syndrome is typically an asymptomatic hemoglobinopathy, which is caused by an autosomal recessive genetic mutation. The Hb Lepore variant, consisting of two normal alpha globin chains (HBA) and two delta-beta globin fusion chains which occurs due to a "crossover" between the delta (HBD) and beta globin (HBB) gene loci during meiosis and was first identified in the Lepore family, an Italian-American family, in 1958. There are three varieties of Hb Lepore, Washington, Baltimore and Hollandia. All three varieties show similar electrophoretic and chromatographic properties and hematological findings bear close resemblance to those of the beta-thalassemia trait; a blood disorder that reduces the production of the iron-containing protein hemoglobin which carries oxygen to cells and which may cause anemia.
Hemoglobin Hopkins-2 is a mutation of the protein hemoglobin, which is responsible for the transportation of oxygen through the blood from the lungs to the musculature of the body in vertebrates. The specific mutation in Hemoglobin Hopkins-2 results in two abnormal α chains. The mutation is the result of histidine 112 being replaced with aspartic acid in the protein's polypeptide sequence. Additionally, within one of the mutated alpha chains, there are substitutes at 114 and 118, two points on the amino acid chain. This mutation can cause sickle cell anemia.
Hemoglobin O (HbO) is a rare type of hemoglobin in which there is a substitution of glutamic acid by lysine as in hemoglobin C, but at different positions. Since the amino acid substitution can occur at different positions of the β-globin chain of the protein, there are several variants. In hemoglobin O-Arab (HbO-Arab) substitution occurs at position 121, while in hemoglobin O-Padova (HbO-Padova) it is at 11 position, and in hemoglobin O Indonesia (HbOIna) it is at 116.
